The major long-term objective of this work is to provide data and knowledge that can be used to maximize the beneficial effects of fluoride and minimize the frequency and degree of unwanted side effects. Previous studies supported by this grant have shown that the levels of fluoride in the oral fluids and the developing enamel are directly related to plasma fluoride levels. Thus, the development and severity of dental fluorosis and perhaps the cariostatic effect of the ion are dependent on the quantitative aspects of fluoride metabolism which determine systemic fluoride levels. Several studies of factors that may influence plasma and other tissue fluoride levels are proposed for the next grant period. The only environmental variable taken into account for the determination of the appropriate water fluoride level for a community is the average regional temperature. One of the proposed studies will further examine the effects of the level of water intake on the balance and tissue levels of fluoride and the prevalence and severity of dental fluorosis. The results of this study will also be relevant to the fluoridation of water supplies for the prevention of dental caries. Another study will examine the balance, tissue levels and pharmacokinetics of fluoride and the prevalence and severity of dental fluorosis in diabetes mellitus and diabetes insipidus. These diseases are associated with high levels of urine output and water intake (therefore fluoride intake) and affect over 12 million U.S. citizens. There is good evidence that the urinary excretion and balance of fluoride are affected by the composition of the diet. These effects will be further examined in chronic feeding studies with rats involving four different grains. Another study with human volunteers will examine the effects of diets that tend to alkalinize or acidify the urine on the pharmacokinetics of fluoride. The results of studies done in the 1940s indicated that the fluoride levels of sweat and urine were similar and that fluoride excretion in sweat was quantitatively important under hot and moist conditions. Using modern analytical techniques, it has been determined that sweat fluoride levels are at least an order of magnitude lower than those of urine so it appears unlikely that there are any conditions under which sweat is an important route for fluoride excretion. Two of the proposed studies will examine this matter.